Cerebellar defect

Dussault, I., Fawcett, D., Matthyssen, A., Bader, J. A. and Giguere, V., 1998, Orphan nuclear receptor ROR alpha-deficient mice display the cerebellar defects of staggerer, Mech Dev, 70, pp 147-53. 

Kahic G, Kaulen P, Briining G, Baumgarten HG, Griisser-Cornehls U (1990) Autoradiographic analysis of benzodiazepine receptors in mutant mice with cerebellar defects. J. Chem. Neuroanat., 3, 261-270. 

Sekerkova G, Ilijic E, Mugnaini E (2004) Bromodeoxyuridine administered during neurogenesis of the projection neurons causes cerebellar defects in rat. J Comp Neurol 470 221-239... 

In cerebellar Purkinje cells, a TTX-sensitive inward current is elicited, when the membrane was partially repolarized after strong depolarization. This resurgent current contributes to high-frequency repetitive firing of Purkinje neurons. The resurgent current results from open channel block by the cytoplasmic tail of the (34 subunit. The med Nav 1.6 mutant mice show defective synaptic transmission in the neuromuscular junction and degeneration of cerebellar Purkinje cells. 

In patients with ataxia-telangiectasia, an autosomal recessive disease in humans resulting in the development of cerebellar ataxia and lymphoreticular neoplasms, there appears to exist an increased sensitivity to damage by x-ray. Patients with Fanconi s anemia, an autosomal recessive anemia characterized also by an increased frequency of cancer and by chromosomal instability, probably have defective repair of cross-linking damage. 

Glutaric acidurias Type I Primary defect of glutarate oxidation Type II Defect of electron transfer flavoprotein Type I Severe basal ganglia/cerebellar disease with macrocephaly. Onset 1-2 years Type II Fulminant neurological syndrome of the neonate. Often with renal/hepatic cysts. Usually fatal Diet low in lysine and tryptophan Supplementation with coenzyme Q, riboflavin, carnitine... 

Diagnosis of a urea cycle defect in the older child can be elusive. Patients may present with psychomotor retardation, growth failure, vomiting, behavioral abnormalities, perceptual difficulties, recurrent cerebellar ataxia and headache. It is therefore essential to monitor the blood ammonia in any patient with unexplained neurological symptoms, but hyperammonemia is inconstant with partial enzymatic defects. Measurement of blood amino acids and urinary orotic acid is indicated. 

Coenzyme Q10 (CoQlO) deficiency. This mitochondrial encephalomyopathy has three main clinical presentations. A predominantly myopathic form is characterized by the triad of exercise intolerance, recurrent myoglobinuria, and CNS involvement. A more frequent ataxic form is dominated by ataxia and cerebellar atrophy, variously associated with weakness, developmental delay, seizures, pyramidal signs, and peripheral neuropathy, often simulating spinocerebellar atrophy. A third presentation with fatal infantile encephalomyopathy and renal involvement, has been described in two families. The biochemical defect (or defects) presumably involve different steps in the biosynthesis of CoQlO, but are still unknown, as are the molecular defects. Diagnosis, however, is important because all patients - and especially those with the myopathic and infantile forms - benefit from CoQlO supplementation [13,14]. 

Central and/or peripheral nervous system involvement is one of the most frequent features, often resulting in the neonatal period in drowsiness, poor sucking, severe hypotonia, abnormal movements, seizures, respiratory distress, and fatal keto-acidotic coma with lactic acidosis [3]. To these severe conditions echo late-onset diseases now frequently attributed to or associated with mitochondrial OXPHOS defects, such as Alzheimer s or Parkinsons disease [10]. Major neurological symptoms, in variable combinations, involve trunk hypotonia, cranial nerve and brainstem involvement (with abnormal eye movements, ophthalmoplegia, recurrent apneas), cerebellar ataxia, myoclonia, seizures, pyramidal syndrome, peripheral neuropathy, poliodystrophy, and leukodystrophy infections [27,28]. A diffuse impairment of the cerebral white matter (leukodystrophy) mostly results in motor disturbance with mental retardation and low incidence of seizures. 

DiPaolo G, Moskowitz HS, Gipson K et al (2004) Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking. Nature 431 415-22 Dittman JS, Regehr WG (1996) Contributions of calcium-dependent and calcium-independent mechanisms to presynaptic inhibition at a cerebellar synapse. I Neurosci 16 1623-33 Diverse-Pierluissi M, Goldsmith PK, Dunlap K (1995) Transmitter-mediated inhibition of N-type calcium channels in sensory neurons involves multiple GTP-binding proteins and subunits. Neuron 14 191-200... 

It is well established that mitochondrial function defects are not severe until the proportion of mutant mtDNA reaches a high level, which forms the basis of the concept of the threshold effect. In skeletal muscle, the level of the A3243G mutation is related to the severity of strokelike episodes, epilepsy, and dementia in patients with MELAS syndrome (C6, H14, PI). Similarly, the level of the A8344G mutation is correlated with the degree of cerebellar ataxia and myoclonus in patients with MERRF syndrome (C6). Thus, molecular genetic analysis of mtDNA mutations in muscle biopsies usually provides more definitive diagnosis of... 

Grady RM, Wozniak DF, Ohlemiller KK, Sanes JR. 2006. Cerebellar synaptic defects and abnormal motor behavior in mice lacking a- and P-dystrobrevin. J Neurosci 26 2841-2851. 

A-6) In xeroderma pigmentosnm there is a defect in the normal DNA repair process. Patients with the disease are susceptible at an early age to developing skin cancer following sun exposure, which can cause abnormal pyrimidine dimers in the DNA molecule. The condition may involve a deficiency in an endonuclease. Ataxia telangiectasia and Fanconi s anemia are conditions that are also believed to be related to endonuclease deficiency. In (he former, there are abnormal proliferation of blood vessels in addition to cerebellar dysfunction. 

The results obtained (M8) suggest that a defective transport of tryptophan is established across the cells of the jejunum and across the proximal renal tubules. The reduced conversion of tryptophan to kynurenine is probably due to a deficiency of tryptophan pyrrolase or to a lower transport of substrate to the enzyme. According to the same authors (M8), the cerebellar ataxia may be ascribable to intoxication by retained indolic acids. 

In 1971, Salen reported (12) that the rare inheirted lipid storage disease, cerebrotendinoux xanthomatosis (CTX), was associated with defective bile acid synthesis. The major and prominent clinical features in CTX syndrome were tendon xanthomas, juvenille cataracts, dementia, pyramidal paresis, cerebellar ataxis, abnormal electroencephalogram (EEC), and cerebral computed tomographic (CT) scans, premature atherosclerosis, pulmonary dysfunction and osteoporosis. Low serum levels of 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 were also detected in these patients in association with osteoporosis and frequent bone fractures (13,14). The disease is inherited as an autosomal recessive trait, but is usually detected in adults when cholesterol and cholestanol have accumulated over many years (13-16). Major biochemical... 

CXCR4 Similar to SDF-la knockout, but also noted defective mesenteric angiogenesis and impaired cerebellar development... 

Herrup K, Mullen RJ (1979) Staggerer chimeras intrinsic nature of Purkinje cell defects and implications for normal cerebellar development. Brain Res., 178, 443 57. 

Mouse CXCR4 No Abnormal Ventricular septal defect Impaired B cell lymphopoiesis Impaired bone marrow myelopoiesis Defective cerebellar and gastric vascular development... 

The clinical picture of deficiencies in glucose utilization can be subdivided into groups in which myopathy is the predominant manifestation or in which brain dysfunction predominates (cerebellar ataxia, pyramidal signs and dementia). In this review, however, we focus on the role of putative defects in energy metabolism as a possible factor in neurodegenerative diseases. 

Kearns-Sayre syndrome Onset before 20 years of age, characterized by opthalmoplegia, atypical retinitis pigmentosa, mitochondrial myopathy, and one of the following cardiac conduction defect, cerebellar syndrome, or elevated CSF proteins. Deletion of contiguous segments of tRNA and OXPHOS polypeptides, or duplication mutations consisting of tandemly arranged normal mtDNA and an mtDNA with a deletion mutation. 

A number of inherited deficiencies of peroxisomal enzymes have been described. Zellweger s syndrome, which results from defective peroxisomal biogenesis, leads to complex developmental and metabolic phenotypes affecting principally the liver and the brain. One of the metabolic characteristics of these diseases is an elevation of C26 0, and C26 1 fatty acid levels in plasma. Refsum s disease is caused by a deficiency in a single peroxisomal enzyme, the phytanoyl CoA hydroxylase that carries out a-oxidation of phytanic acid. Symptoms include retinitis pigmentosa, cerebellar ataxia, and chronic polyneuropathy. Because phytanic acid is obtained solely from the diet, placing patients on a low-phytanic acid diet has resulted in marked improvement. 

A patient presented with dysmorphia and cerebellar degeneration. Analysis of his blood indicated elevated levels of phytanic acid and very-long-chain fatty acids, but no elevation of palmitate. His symptoms are consistent with a defect in an enzyme involved in which of the following ... 

---